Thursday, March 25, 2021
Researchers at the National Institutes of Health (NIH) have discovered specific regions within the DNA of neurons that accumulate certain types of damage (called single-stranded breaks, or SSBs). This accumulation of SSB appears to be unique to neurons and challenges what is generally understood about the cause of DNA damage and its possible implications in neurodegenerative diseases.
Because neurons require considerable amounts of oxygen to function properly, they are exposed to high levels of free radicals, toxic compounds that can damage DNA within cells. Typically, this damage occurs randomly. However, in this study, damage within neurons was often found within specific regions of DNA called “enhancers” that control the activity of nearby genes.
Fully mature cells, like neurons, do not need all of their genes to be active at the same time. One way that cells can control gene activity involves the presence or absence of a chemical tag called a methyl group on a specific building block of DNA. Closer inspection of the neurons revealed that a significant amount of SSB was produced when the methyl groups were removed, generally making that gene available to be turned on.
One explanation proposed by the researchers is that removing the methyl group from DNA creates an SSB, and neurons have multiple repair mechanisms ready to repair that damage as soon as it occurs. This challenges the common wisdom that DNA damage is inherently a process that must be prevented. Instead, at least in neurons, it is part of the normal process of turning genes on and off. Furthermore, it implies that defects in the repair process, not the DNA damage itself, can potentially lead to developmental or neurodegenerative diseases.
This study was made possible through collaboration between two NIH laboratories: one led by Michael E. Ward, MD, Ph.D. at the National Institute of Neurological Disorders and Stroke (NINDS) and the other by Andre Nussenzweig, Ph.D. at the National Cancer Institute (NCI). Dr. Nussenzweig developed a method to map DNA errors within the genome. This highly sensitive technique requires a considerable number of cells to function effectively, and Dr. Ward’s laboratory provided the expertise to generate a large population of neurons using induced pluripotent stem cells (iPSCs) derived from a human donor. Keith Caldecott, Ph.D. at the University of Sussex he also provided his expertise in single strand break repair pathways.
The two labs are now looking more closely at the repair mechanisms involved in reversing neuronal SSBs and the possible connection to neuronal dysfunction and degeneration.
Michael E. Ward, MD, Ph.D., researcher, NINDS
Andre Nussenzweig, Ph.D., chief, Genomic Integrity Laboratory, NCI
Wu W. et al. Neural enhancers are hot spots for repairing single strand DNA breaks. March 25, 2021. Nature. DOI: 10.1038 / s41586-021-03468-5
This study was supported by the NIH / NINDS / NCI Intramural Research Programs, an NIH Intramural FLEX Award, the U.S. Department of Defense, the Chan Zuckerberg Initiative, the Packard ALS Center, the Alex’s Foundation Lemonade Stand, UK Medical Research Council, Cancer Research-UK, ERC Advanced Investigator Award, Royal Society Wolfson Research Merit Award and Ellison Medical Foundation Senior Scholar Award in Aging.
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